The MRI, Genetics and Cognitive Precursors of AD and Dementia was initiated in response to evidence implicating cerebrovascular risk factors (CVRF) in cognitive decline, AD and dementia. In the initial study phase, we quantified regional, total brain and white matter hyperintensity (WMH) volumes, ascertained the presence or absence of Silent Cerebral Infarcts (SCI) and measured cognitive performance (NP) in more than 2,900 subjects of the Framingham Offspring and Omni Cohorts. Cross-sectional findings indicate that CVRF predispose to diminished cognitive performance by way of vascular brain injury. Our initial findings are in concert with previous reports from epidemiological and clinical studies suggesting that CVRF burden is associated with lowered cognitive performance. We now propose to extend our study by determining changes in brain structure and function by repeating the MR and NP measurements in these subjects. Longitudinal data will enable us to further explore the hypothesis that CVRF prospectively ascertained during mid-life play an important role in progressive brain injury leading in turn to progressive decline in cognition, increasing the likelihood of mild cognitive impairment (MCI) or dementia in later life. In addition, the rich family structure of the Framingham cohorts, and the accumulated wealth of family-based genetic data will facilitate analyses of genetic influences on these measures. To achieve this goal, we have added MRI measures of hippocampus and entorhinal cortex to assess brain areas affected by Alzheimer's disease (AD) in order to contrast the impact of CVRF with the AD process amongst the older members of the cohort. In addition, we have implemented brain mapping techniques for cross-sectional and longitudinal analyses. These new MRI analyses will be combined with measures of subclinical vascular disease as well as ascertainment of an expanded number of novel risk factors such as serum homocysteine. Older individuals with mild cognitive impairment (MCI) will also be identified to explore the relationship between CVRF, MRI changes and clinically relevant cognitive impairments. Finally, we will use the extensive genetic information to identify younger individuals with a documented family history of dementia to explore potential early changes in brain structure and cognition that may be under genetic influence. These data will be used to test the hypotheses that CVRF and indices of subclinical vascular disease will be associated with accelerated decline in cognitive function resulting from progressive brain injury. When left untreated, we also hypothesize that CVRF will lead to clinically relevant cognitive impairment such as MCI and dementia. Finally, we hypothesize that for individuals at genetic risk, these processes may begin earlier in life. Since control of CVRF clearly prevents clinical stroke, it is hoped that data from this study will encourage control of CVRF and reduce the likelihood of cognitive decline and dementia.